Understanding Biomarkers in Neurological Disorders

A paper, published in Nature Reviews Neurology, highlights neurofilament proteins, and particularly neurofilament light chain (NfL), which have become one of the most intensely studied blood-based biomarkers in neurological and neuropsychiatric diseases. Specifically, the current value and potential clinical applications of neurofilaments as a biomarker of neuro-axonal damage in a range of brain diseases, including multiple sclerosis, Alzheimer disease, frontotemporal dementia, amyotrophic lateral sclerosis, stroke and cerebrovascular disease, traumatic brain injury, and Parkinson disease. The capacity of NfL to reflect, in real time, neuro-axonal injury as the substrate of persistent disability has attracted many researchers from basic, translational and clinical sciences to explore the potential of neurofilaments for use in epidemiological studies, in the diagnostic work-up of individuals and as an end point in clinical trials. One particular advantage of NfL is that its concentrations in plasma or serum reflect neuronal damage as effectively as its levels in CSF, enabling minimally invasive longitudinal monitoring of the biomarker and giving it great potential for clinical application. Use of NfL in clinical practice has become closer to reality owing to the establishment of large reference databases for physiological serum levels in adults and children, which enable more precise interpretation at the individual level rather than just at the group level. Nevertheless, differences between serum and plasma preparations preclude the use of reference values for both matrices equally. Similarly, the various high-sensitivity assay platforms that are expected to be launched for clinical use generate different absolute values of NfL, which precludes comparison of data generated with different platforms until reference ‘exchange rates’ are established. Current evidence suggests that serum samples are preferable to plasma samples for measurement of NfL in large-scale clinical laboratories as they provide the same biological information but the production of serum samples is simpler and more easily standardized. Nature Portfolio Springer Nature Group #neuroscience #neurology #psychiatry #dementia #neurodegeneration #axon #neurons #glia #biomarker #blood #plasma #precisionmedicine #alzheimers #alzheimersdisease #multiplesclerosis #als #cerebrovascular #parkinsonsdisease #stroke #braintrauma #diagnostics #earlydetection #earlydiagnosis #aging #CSF #fluidbiomarkers #liquidbiopsy #pathology #cognitivedecline #cognitiveimpairment #neurologicaldisorders #neurodegenerativedisease #brainpathology #neuropathology https://lnkd.in/efXYTbCZ

Blood-based #biomarkers are critical for our ability to detect disease and to determine whether a treatment is working. For example, we use blood cholesterol levels to assess a person's risk for heart disease and to determine whether an intervention (diet, exercise, medication...) is working. We are now starting to identify blood-based biomarkers for #neurodegenerativediseases -- and these tools promise to revolutionize everything from #preclinicalresearch and #clinicaltrials to how we treat patients. In #alzheimersdisease we are learning that phosphorylated #tau protein, specifically pT217, can improve screening accuracy for clinical trials and may serve as a prognostic biomarker of disease (here's a recent publication as an example: https://lnkd.in/gYcyQ4Zd). Earlier this year we learned about an assay that measures alpha-synuclein seeding as a biomarker for #parkinsonsdisease (https://lnkd.in/gpwVpzEy). Additional research is identifying biomarkers for ALS, dementia, and other diseases. As these measurements are incorporated into clinical trials, they will enable shorter trial durations and more accurate assessment of outcomes. And when they are incorporated into standard practice in the treatment of patients with these diseases, they will help doctors identify patients who are likely to benefit from available therapies and to determine whether those therapies are working.

EARLY BIOMARKERS OF ALZHEIMER;S DISEASE BY PRE-TANGLE SOLUBLE TAU ASSEMBLIES A new biomarker test has been developed that can detect early-stage tau protein clumping up to a decade before it is visible on brain scans, thereby improving early Alzheimer's (AD) diagnosis. Unlike amyloid-beta, tau neurofibrillary tangles are directly linked to cognitive decline. According to research published the University of Pittsburgh, this biomarker test can identify small amounts of tau protein prone to clumping, as well as its misfolded pathological forms, in the brain, cerebrospinal fluid, and potentially blood, long before they appear on brain scans in Alzheimer's patients. This cerebrospinal fluid test correlates with the severity of cognitive decline, regardless of brain amyloid deposition, providing a potential pathway for early diagnosis and intervention. Most biomarker research has prioritized detecting amyloid-beta changes since abnormalities in amyloid-beta typically emerge before tau pathology in AD. However, the clumping of tau protein into well-ordered structures, known as "neurofibrillary tangles," is more strongly associated with the cognitive changes observed in affected individuals, making it a more defining event for AD. Neurofibrillary tangles (NFTs), composed of paired helical filaments (PHFs) or straight filaments formed by the polymerization of tau protein into fibrillar intracellular aggregates, are a key neuropathological feature of AD. In AD, the severity of tau pathology, evaluated using the Braak staging for NFTs, is a more reliable correlate and predictor of cognitive outcomes compared to amyloid beta (Aβ) plaques, another hallmark of AD. Evidence suggests that physiological buffer-soluble, low-order tau assemblies (such as oligomers and protomers, collectively known as soluble tau assemblies or STAs) form during the initial stages of the tau aggregation cascade and serve as the building blocks for higher-order fibrils and neurofibrillary tangles (NFTs). These STAs are highly effective at seeding and propagating tau toxicity. This indicates that early-stage STAs could be useful as early diagnostic biomarkers and targets for effective anti-tau therapeutics. The study utilized an integrative approach to identify a core sequence of soluble tau assemblies (STAs) in TBS extracts of human AD brain tissue. The research team demonstrated that the STA core region rapidly aggregates in vitro and significantly alters neuronal excitability and discovered aggregation-relevant phosphorylation sites, p-tau262 and p-tau356, which are detectable in the pre-neurofibrillary tangle (NFT) stage. The LC-MS/MS analysis revealed that the STA core region-containing tau forms were near-full-length and included mid-region and microtubule-binding region sequences. Overall, these new insights verified pathological Phospho-tau serine-262 and serine-356 clinical performance as an early AD biomarker. #https://lnkd.in/e6fPBmse

Large-scale Plasma Proteomic Profiling Unveils Diagnostic Biomarkers and Pathways for Alzheimer's Disease A large-scale study examined nearly 7,000 plasma proteins from 1,270 people with clinical Alzheimer's disease (AD) and 2,096 cognitively normal individuals. We identified 456 significant aptamers (416 proteins) that showed consistent results in both discovery and replication stages, that were further validated using two external datasets, confirming their reliability. Among the 416 proteins identified in the study, including 168 proteins (193 aptamers) novel proteins associated with Alzheimer's disease (AD). These included proteins like SPC25, CLU, and PPBP involved in signal transduction, and SPARC, NCAM1, and VEGFA involved in endothelial pathways. Additionally, 122 proteins (123 aptamers) from this study have support from previous plasma studies. Since blood collection is minimally invasive, developing blood-based biomarkers would be ideal. Plasma ptau217 is very effective at predicting amyloid positivity but is a proxy for brain amyloidosis, not overall dementia. New anti-Aβ therapies can remove Aβ deposits as seen in amyloid PET scans, and studies show ptau217 levels decrease with amyloid removal, even if neurodegeneration continues. Therefore, additional biomarkers beyond tau and Aβ are needed to track overall disease status and learn whether they could be employed to develop innovative predictive models. In order to develop Aβ and tau-independent biomarkers, we used AI to identify seven-proteins that predicted clinical AD and biomarker status. This model was further validated in orthogonal platforms including Alamar and Olink and replicated in four independent cohorts. Further analysis of the predictive performance of this model with other non-AD dementia was examined and showed low overlap with Parkinson’s Disease (PD) and Dementia with Lewy Bodies (DLB), but not with Frontotemporal Dementia (FTD). Larger studies on these groups are needed to create disease-specific predictive models to better assess how specific the current model is for Alzheimer's disease. We performed pathway analysis of the 416 AD-associated plasma proteins provided insights into the biological mechanisms of AD. Although the enriched pathways seem to cover general processes like blood homeostasis and extracellular matrix signaling, a detailed analysis shows they also involve relevant endothelial and neuronal proteins. Key pathways included lipid metabolism, immune and hemostatic response, extracellular matrix, and neuronal signaling. These analyses show that endothelial cell dysfunction can cause blood-brain barrier issues, leading to brain proteins leaking into the blood. To read the full article, go to: https://lnkd.in/d-J-gMyn